This grant proposal is in response to RFA 87-HL-06-H Postmenopausal Estrogen/Progestin Interventions. In it we propose to study 150 postmenopausal patients using a randomized, prospective, three-way factorial, possibly doubled blind study design. Issues to be addressed are estrogen usage (present versus absent), route of administration (oral versus transdermal), dosage (low versus high) and combination therapy with a progestin (present versus absent). Patients will be studied at baseline and at 6-month intervals for 3 years on therapy. End points to be assessed are endocrine (serum estradiol, estrone, estrone sulfate, and medroxyprogesterone acetate levels), cardiovascular (chest pain questionnaire, resting EKG, exercise stress EKG, and thallium scintigraphy), lipids (circulating total cholesterol, triglycerides, LDL, HDL, HDL2/HDL3 subfractions, Apo B, E, A- 1, A-2, and Apo E phenotyping), coagulation (plasma fibrinogen, factor VII, antithrombin III activity, fibrinogen D-dimer, fibrin degradation products, fibrinopeptide A, and high molecular weight fibrinogen), hypertension (red cell cation transport, plasma renin activity, normal and high molecular weight renin substrate, and aldosterone), skeleton (serum calcium, phosphate, creatinine, mid- segment PTH, 25(OH) and 1,25(OH) vitamin D, alkaline phosphatase, and osteocalcin; urinary calcium, hydroxyproline and creatinine; and lumbar and femoral neck bone mass by dual photon absorptiometry), endometrium (standard histological assessment, computerized digital imaging and estrogen receptor localization), gallbladder (ultrasound) and breast (physical examination and mammography). These studies will comprehensively assess the impact of hormone replacement on end points believed to be related to heart disease, as well as other proposed benefits and risks of this form of therapy.